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WO1993016066A1 - Composes d'abaissement du cholesterol - Google Patents

Composes d'abaissement du cholesterol Download PDF

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Publication number
WO1993016066A1
WO1993016066A1 PCT/US1993/001061 US9301061W WO9316066A1 WO 1993016066 A1 WO1993016066 A1 WO 1993016066A1 US 9301061 W US9301061 W US 9301061W WO 9316066 A1 WO9316066 A1 WO 9316066A1
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WIPO (PCT)
Prior art keywords
compound
effective amount
therapeutically effective
pharmaceutically acceptable
measured
Prior art date
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PCT/US1993/001061
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English (en)
Inventor
Henry Joshua
Guy H. Harris
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Merck and Co Inc
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Merck and Co Inc
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Filing date
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Publication of WO1993016066A1 publication Critical patent/WO1993016066A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid
  • sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
  • MEVACOR ® (lovastatin), now commercially available, is one of a group of very active
  • antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase.
  • Squalene synthetase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
  • isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase.
  • Zaragozic acid C This compound is produced by a solid fermentation employing a culture of Leptodontium elatius.
  • the present invention discloses certain structurally related compounds to Zaragozic acid C which have now been isolated from a fermentation broth using
  • the present invention is directed to compounds of structual formula (I)
  • R 1 is selected from the group consisting of ;
  • Z 1 , Z 2 and Z 3 are each independently selected from; a) H;
  • a second class of this invention are those compounds of formula (I) wherein R 1 is Further exemplifying this class is the compound wherein Z 1 , Z 2 and Z 3 are each hydrogen or a pharmaceutically acceptable salt thereof.
  • the compound wherein Z 1 , Z 2 and Z 3 are each hydrogen is hereafter referred to as Zaragozic acid E.
  • the compounds of formula (I) are prepared in an aerobic fermentation procedure employing a fungal culture, MF5465, identified as Leptodontium elatius.
  • the fermentation procedure employed is described in U.S. Patent 5,026,554, the contents of which are herein specifically incorporated by reference.
  • the compounds of the present invention have been isolated as components produced in lower yield then Zaragozic acid C from this fermentation procedure.
  • Mutants of MF5465 having essentially the same characteristics as MF 5465, are also capable of producing compounds of this invention.
  • the culture MF5465 is that of a fungus, a lignicolous Hyphomycete, Leptodontium elatius, isolated from wood in the Joyce Kilmer Memorial Forest in North Carolina. This culture has been deposited with the American Type Culture Collection at 12301 Parklawn Drive, Rockville, MD 20852 as ATCC 74011.
  • Nutrient media may also contain mineral salts and defoaming agents.
  • the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, glycerin, starch, dextrin, and the like. Other sources which may be included are maltose, mannose, sucrose, and the like. In addition, complex nutrient sources such as oat flour, corn meal, millet, corn and the like may supply utilizable carbon.
  • the exact quantity of the carbon source which is used in the medium will depend, in part, upon the other ingredients in the medium, but is usually found in an amount ranging between 0.5 and 5 percent by weight. These carbon sources can be used individually in a given medium or several sources in combination in the same medium.
  • the preferred sources of nitrogen are amino acids such as glycine, methionine, proline, threonine and the like, as well as complex sources such as yeast extracts (hydrolysates, autolysates), dried yeast, tomato paste, soybean meal, peptone, corn steep liquor, distillers solubles, malt extracts and the like.
  • amino acids such as glycine, methionine, proline, threonine and the like
  • complex sources such as yeast extracts (hydrolysates, autolysates), dried yeast, tomato paste, soybean meal, peptone, corn steep liquor, distillers solubles, malt extracts and the like.
  • Inorganic nitrogen sources such as ammonium salts (eg. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.) can also be used.
  • ammonium salts eg. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • nitrogen can be used alone or in combination in amounts ranging between 0.2 to 70 percent by weight of the medium.
  • the carbon and nitrogen sources are generally employed in combination, but need not be in pure form. Less pure materials which contain traces of growth factors, vitamins, and mineral nutrients may also be used.
  • Mineral salts may also be added to the medium such as (but not limited to) calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, magnesium salts, copper salts, cobalt salts and the like. Also included are trace metals such as
  • a defoaming agent such as polyethylene glycol or silicone may be added,
  • the preferred process for production of compounds of this invention consists of inoculating spores or mycelia of the producing organism into a suitable medium and then cultivating under aerobic condition.
  • the fermentation procedure generally is to first inoculate a preserved source of culture into a nutrient seed medium and to obtain, sometimes through a two step process, growth of the organisms which serve as seeds in the production of the active compounds.
  • the flasks are incubated with agitation at temperatures ranging from 20 to 30°C, preferably 25 to 28oC. Agitation rates may range up to 400 rpm, preferably 200 to 220 rpm.
  • Seed flasks are incubated over a period of 2 to 10 days, preferably 2 to 4 days. When growth is plentiful, usually 2 to 4 days, the culture may be used to inoculate production medium flasks.
  • a second stage seed growth may be employed, particularly when going into larger vessels. When this is done, a portion of the culture growth is used to inoculate a second seed flask incubated under similar conditions but employing shorter time.
  • the fermentation production medium is incubated for 3 to 30 days, preferably 7 to 21 days, with or without agitation (depending on whether liquid or solid fermentation media are employed).
  • the fermentation is conducted aerobically at temperatures ranging from 20 to 40°C. If used, agitation may be at a rate of 200 to 400 rpm. To obtain optimum results, the temperatures are in the range of 22 to 28oC, most preferably 24 to 26°C.
  • the pH of the nutrient medium suitable for producing the active compounds is in the range of 3.5 to 8.5, most preferably 5.0 to 7.5. After the appropriate period for production of the desired compound, fermentation flasks are harvested and the active compound isolated.
  • a water miscible organic solvent is employed to extract a compound of this invention from the solid fermentation medium.
  • the preferred solvent for extraction of the solid fermentation is acetone.
  • the mixture of organic solvent and fermentation broth is vigorously stirred and filtered, and water added to the filtrate.
  • the aqueous extract is then adsorbed on an anion exchange resin.
  • the preferred resin is AG4-X4 (formate).
  • the active compound can be eluted from AG4-X4 using a low pH solution or a high salt eluant; the preferred eluant is 0.2N sulfuric acid in 60% acetonitrile water. After elution from the ion
  • the active compound may be recovered from the eluate by diluting the eluate with water, and extracting into an organic solvent; the preferred solvent for extraction is ethyl acetate. The organic extract is then evaporated to afford partially purified active compound.
  • the active compound is further purified by chromatographic separation which may be carried out by employing reverse phase chromatography.
  • the preferred adsorbent for this chromatography is a C8 bonded phase silica gel.
  • the preferred eluant for reverse phase chromatography is a mixture of acetonitrile and water buffered at a low pH, such as 0.1% phosphoric acid, or trifluoroacetic acid.
  • the present invention is also directed to a method of treating hypercholesterolemia which comprises the administration to a subject in need of such
  • the compounds of this invention are useful as antihypercholesterolemic agents for the treatment of arteriosclerosis, hyperlipidemia, familial hypercholesterolemia and the like diseases in humans. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients, but daily dosage for adults is within a range of from about 20 mg to 2000 mg (preferably 20 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably employed as required.
  • the present invention is also directed to a method of inhibiting squalene synthetase which
  • the compounds of this invention are useful in treating disease conditions such as, but not limited to, hypercholesterolemia which result from the action of the enzyme squalene synthetase. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients, but daily dosage for adults is within a range of from about 20 mg to 2000 mg (preferably 20 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably employed as required.
  • the pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)
  • the compounds of this invention may also be administered in combination with other cholesterol lowering agents such as those which inhibit an
  • Example of such agents would include but are not limited to HMG-CoA reductase inhibitors, HMG-COA synthase inhibitors, and squalene expoxidase
  • inhibitors include lovastatin, simvastatin, pravastatin and fluvastatin.
  • Other cholesterol lowering agents that may be
  • niacin niacin
  • probucol niacin
  • gemfibrozil niacin (2-8 gm)
  • probucol up to 1000 mg
  • clofibrate up to 2 gm
  • the compounds of this invention may also be coadministered with pharmaceutically acceptable
  • nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract.
  • examples of such polymers include cholestyramine, colestipol and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide].
  • the relative amounts of the compounds of this invention and these polymers is between 1:100 and 1:15,000.
  • mice Male, Charles River CD rats (120 to 150 g) were fed a diet containing 0.1% lovastatin for 4 days. The livers from these rats were homogenized in 5 volumes (ml/g) of ice cold 50 mM HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 5 mM
  • EDTA ethylenediaminetetraacetic acid pH 7.5 with a Potter-Elvehjem type tissue grinder.
  • the homogenate was centrifuged twice at 20,000 ⁇ g for 15 minutes at 4°C, discarding the pellet each time. The supernatant was then centrifuged at 100,000 ⁇ g for 1 hour at 4°C.
  • the resulting microsomal pellet was resuspended in a volume of the above homogenizing buffer equal to one-fifth the volume of the original homogenate.
  • This microsomal preparation has a protein concentration of about 7 mg/ml.
  • the microsomal suspensions were stored in aliquots at -70°C. Squalene synthetase activity in these aliquots is stable for at least several months.
  • Prenyl transferase was assayed by the method of Rilling (Methods in Enzymology 110, 125-129 (1985)) and a unit of activity is defined as the amount of enzyme that will produce 1 ⁇ mole of farnesyl
  • livers of 23 forty-day old male rats that had been fed 5% cholestyramine plus 0.1% lovastatin were homogenized in a Waring blender in 1 liter of 10 mM mercaptoethanol, 2 mM EDTA, 25 ⁇ M leupeptin, 0.005% phenylmethyl sulfonyl fluoride pH 7.0 containing 0.1 trypsin inhibitor units of aprotinin/ml.
  • This supernatant was adjusted to pH 7.0 with 3N KOH and a 35-60% ammonium sulfate fraction taken.
  • the 60% pellet was redissolved in 60 ml of 10 mM potassium phosphate, 10 mM mercaptoethanol, 1 mM EDTA pH 7.0 (Buffer A) and dialyzed against two 1 liter changes of Buffer A. This dialyzed fraction was applied to a 12.5 ⁇ 5 cm column of DEAE-sepharose 4B equilibrated with Buffer A. The column was washed with 700 ml of Buffer A and a 1 liter gradient from Buffer A to 100 mM potassium phosphate, 10 mM mercaptoethanol, 1 mM EDTA pH 7.0.
  • [4- 14 C]farnesyl-pyrophosphate and its activity was stable stored at 4oC for at least 6 months.
  • the solvent (ethanol: 0.15 N NH 4 OH, 1:1) was removed from 55 ⁇ Ci of [4- 14 C] isopentenyl pyrophosphate(47.9 ⁇ Ci/ ⁇ mole) by rotary evaporation.
  • Geranyl-pyrophosphate 250 ⁇ l of a 20 mM solution, and 50 ⁇ l of the ammonium sulfate suspension of prenyl transferase were added to initiate the reaction.
  • This incubation contained 5 ⁇ moles of geranyl pyrophosphate, 1.15 ⁇ moles of isopentenyl pyrophosphate, 6 ⁇ moles of MgCl 2 of 0.18 units of prenyl transferase in a volume of 900 ⁇ l. The incubation was conducted at 37oC.
  • [4- 14 C]farnesyl pyrophosphate The [4- 14 C]farnesyl pyrophosphate was stored in aliquots at -70°C. Sq ⁇ alene Synthetase Assay
  • synthetase inhibitors were prepared either in DMSO or MeOH and a 1:120 dilution of the microsomal protein was made with the original homogenizing buffer. For each reaction, 87 ⁇ l of the assay mix was taken with 3 ⁇ l of an inhibitor solution (DMSO or MeOH in the controls), warmed to 30oC in a water bath and then the reaction was initiated by the addition of 10 ⁇ l of the 1:120 dilution of microsomal protein (0.6 ⁇ g protein total in the assay). The reactions were stopped after 20 minutes by the addition of 100 ⁇ l of a 1:1 mix of 40% KOH with 95% EtOH.
  • the stopped mix was heated at 65oC for 30 minutes, cooled, 10 ml of heptane was added and the mix was vortexed. Two g of activated alumina was then added, the mix vortexed again, the alumina allowed to settle and 5 ml of the heptane layer was removed. Ten ml of scintillation fluid was added to the heptane solution and radioactivity was determined by liquid scintillation counting.
  • Percent inhibition is calulated by the formula:
  • IC 50 values were determined by plotting the log of the concentration of the test compound versus the percentage inhibition.
  • the IC 50 is the
  • Representative compounds of this invention exhibited IC 50 values which were all ⁇ 5nM.
  • the present compounds also demonstrate broad spectrum antifungal activity as determined by broth and agar dilution methods.
  • the present invention is also directed to a method of treating fungus infections which comprises the administration to an organism in need of such treatment a nontoxic therapeutically effective amount of a compound represented by the structural formula (I) and pharmaceutically acceptable salts thereof.
  • a compound represented by the structural formula (I) and pharmaceutically acceptable salts thereof Generally from 2 to about 20 mg/kg should be employed as a unit dosage in an antifungal treatment.
  • the compounds of the present invention have been found to be inhibitors of
  • Farnesyl-protein transferase activity may be reduced or completely inhibited by adjusting the compound dose.
  • the intrinsic farnesyl-protein transferase (FTase) activity of representative compounds of this invention is measured by the assays described below:
  • Farnesyl-protein transferase (Ftase) from bovine brain is chromatographed on DEAE-Sephacel
  • Farnesyl-protein transferase (Ftase) from bovine brain was chromatographed on DEAE-Sephacel (Pharmacia, 0-0.8 M NaCl gradient elution), N-octyl agarose (Sigma, 0-0.6 M Nacl gradient elution), and a mono Q HPLC column (Pharmacia, 0-0.3 M NaCl gradient).
  • Ras-CVLS at 1.0 ⁇ M, 0.5 ⁇ M [ 3 H]FPP, and the indicated compounds were incubated with this partially purified enzyme preparation.
  • the Ftase data is a measurement of the ability of the test compound to inhibit Ras farnesylation in vitro.
  • compositions containing the compounds of structural formula I inhibit
  • cancers patients for use in the treatment of cancer.
  • examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
  • the present invention also encompasses a method of the treatment of cancer, comprising the administration of a pharmaceutical composition
  • compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g. saline, at a pH level, e.g., 7.4.
  • pharmacologically acceptable carriers e.g. saline
  • the solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a human patient undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight of a mammal per day, preferably of between 0.5 mg/kg of body weight to about 10 mg/kg of body weight of a mammal a day.
  • Flasks were incubated statically at 25°C for 22 days. Flasks were harvested as follows: 50 mis acetone were added to each production flask; growth was manually broken apart into small fragments by use of a glass pipette; flasks were re-stoppered and placed onto a gyrotory shaker and agitated for 30 minutes at 220 rpm while the extraction proceeded.
  • Fermentation batches as described above were extracted with acetone and then combined and filtered to give 11 L of extract.
  • a portion of the extract (9.5 L) was concentrated under reduced pressure to 4.8 L.
  • the concentrated aqueous acetone extract was then loaded onto an ion exchange column (125 ml resin bed; BioRad AG4-X4; formate cycle; pH 4.5) with a flow rate of 10-15 ml/min.
  • the column was then washed with 1 L of 60 mM sodium formate in 60:40 acetonitrile/water (pH 4.5).
  • the sodium formate solution was prepared as follows. A 2 N formic acid, solution in water was adjusted to pH 3 with NaOH.
  • 13 C (125 MHz): 173.10, 172.53, 170.25, 168.57, 143.92, 142.75, 138.84, 130.21 (2), 129.41 (2), 129.26 (2), 129.10 (2), 127.61, 126.64 (2), 107.38, 90.98, 82.04, 81.25, 76.63, 75.66, 44.65, 37.83, 37.68, 37.62, 36.92, 36.62, 36.22, 35.38, 30.50, 28.78, 28.42, 24.04, 21.23, 19.82.
  • a solution of 0.1 mmol of the free acid of a compound of formula (I) in 10 ml of methanol is treated with an aqueous or methanolic solution containing 0.3 mmol of potassium hydroxide. Evaporation of the solvent affords the tri-potassium salt. Addition of between 0.1 and 0.3 mmol of potassium hydroxide yields analogously mixtures of the mono-potassium,
  • di-potassium and tri-potassium salts whose composition depends upon the exact amount of potassium hydroxide added.
  • the procedure can also be applied to the preparation of the N,N"-dibenzylethylenediamine salt.
  • a solution of 0.1 mmol of the free acid of a compound of formula (I) in 20 ml of 6:4 methanol/ water is treated with an aqueous solution of 0.1 to 0.3 mmol of L-arginine. Evaporation of the solvent affords the title salt, the exact composition of which is determined by the molar ratio of amino acid to the free acid of formula (I) used.
  • Example 9 is also suitable for the preparation of other ester derivatives such as 1) ethyl and other lower alkyl esters and 2) benzyl and

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Abstract

De nouveaux acides zaragoziques ont été isolés d'une culture de MF5465. Ces composés et leurs dérivés sont actifs en tant qu'inhibiteurs de la synthétase du squalène et sont utiles dans le traitement de l'hypercholestérolémie.
PCT/US1993/001061 1992-02-10 1993-02-05 Composes d'abaissement du cholesterol Ceased WO1993016066A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/833,282 US5262435A (en) 1992-02-10 1992-02-10 Cholesterol lowering compounds
US833,282 1992-02-10

Publications (1)

Publication Number Publication Date
WO1993016066A1 true WO1993016066A1 (fr) 1993-08-19

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US (1) US5262435A (fr)
AU (1) AU3658393A (fr)
WO (1) WO1993016066A1 (fr)

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WO1992012160A1 (fr) * 1991-01-09 1992-07-23 Glaxo Group Limited Cetals cycliques pontes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009135979A1 (fr) 2008-05-06 2009-11-12 Consejo Superior De Investigaciones Científicas Procédé d'obtention d'acide zaragocique et de dérivés de celui-ci

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